Jerry L. Bauman

Research from JAMA Internal Medicine — A Method of Determining the Dose of Digoxin for Heart Failure in the Modern Era

Because of the common use of digoxin and because of its narrow therapeutic index, digoxin toxicity has been prevalent historically and, therefore, most clinicians are well aware of the classical dose/concentration-related signs and symptoms of toxicity. Yet, in the modern era the incidence of digoxin toxicity has been declining for a variety of reasons, including a new (lower) therapeutic range, the development of more effective drug therapies for heart failure, and more accurate dosing methods. In addition, digoxin toxicity, once commonly fatal, can now be quickly and effectively treated by the emergency administration of antidigoxin Fab fragments. Indeed, it may be possible to expand the use of Fab fragments to select patients with non-life-threatening digoxin toxicity, in order to save costs and improve patient comfort. Most cases of digoxin toxicity are caused by inappropriately high dosages, which are usually prescribed in the setting of renal dysfunction, while other cases can be attributed to system errors such as multiple prescriptions, poor patient counseling, or errors in transcribing. With modern computerized prescribing systems, such as direct physician order entry and prompts that alert the clinician to the potential for error, it is possible to decrease the incidence of digoxin toxicity even further. A realistic goal is to nearly eradicate once commonplace digoxin toxicity or at least make its occurrence a rare event.

Heart failure is a growing public health problem in the United States, and the approach to the treatment of heart failure has undergone a radical transformation in the past decade. The use of β-blocker therapy in heart failure patients is now widely recommended, based on evidence from large-scale clinical trials demonstrating that bisoprolol, carvedilol, and extended-release metoprolol succinate significantly reduce morbidity and mortality in patients with heart failure. Although these agents appear to provide similar benefits, the question remains whether pharmacologic differences among them could translate to differences in clinical outcomes. The Carvedilol Or Metoprolol European Trial (COMET) compared nonselective blockade of the β₁-/β₂-/α₁-adrenergic receptors with carvedilol versus selective β₁-blockade with immediate-release metoprolol tartrate in patients with chronic heart failure. The trial found that carvedilol significantly reduced all-cause mortality compared with immediate-release metoprolol tartrate, although there were no differences in hospitalizations. Herein we review the pharmacokinetics and pharmacodynamics of metoprolol and carvedilol. In doing so, several issues regarding the design of COMET are identified that could alter the interpretation of the results of this trial. These include the choice of dose and dosage regimen of immediate-release metoprolol tartrate, a dosage form that has never been shown to reduce mortality in patients with heart failure. Additional studies are needed to fully understand whether there are any advantages of selective versus nonselective adrenergic blockade and whether there are any clinically meaningful differences in effectiveness between β-blockers with proven benefit in the management of chronic heart failure. The results of COMET demonstrate that all β-blockers and dosage forms are not interchangeable when prescribed for heart failure. Clinicians should choose only those agents (and dosage forms) that have been proven to reduce mortality in this patient population.

The costs of digoxin toxicity to the US healthcare system have not been previously reported. Therefore, the 1994 database of the US University Health-System Consortium (UHC) was searched for cases of...